Alcohol consumption is an established risk factor for colorectal cancer. However, it is not clear what the biological mechanisms are and if there are susceptible sub-populations. Building on the initial finding that a positive association between alcohol intake and colon cancer was largely restricted to women with a positive family history of colorectal cancer, we propose to characterize the dose-response and timing of the association to examine the modifying role of inherited factors in relation to colorectal adenoma and colorectal cancer risk. If alcohol operates through the one-carbon metabolism pathways, it is plausible that the influence of alcohol intake on colorectal carcinogenesis may have weakened after folate fortification of grain products, which was largely in place since 1996. Because most epidemiologic studies on alcohol and colorectal adenoma/cancer have been conducted in populations with follow-up prior to folate fortification, we propose to evaluate whether the association between alcohol and colorectal adenoma/cancer would be as strong as post fortification. Even if the overall association is weakened after the fortification, the positive association between alcohol consumption and colorectal adenoma/cancer may still persist among particularly susceptible populations. Those with family history of colorectal cancer may be one of the susceptible populations. Other susceptible populations include those with methylene-tetrahydrofolate reductase (MTHFR) 677 variant genotype and those with low intake of other nutrients involved in one-carbon metabolism, including vitamins B6 and B12, methionine, choline, and betaine. We have large prospective studies of women and men with existing data on alcohol consumption and drinking pattern and over 6,000 colorectal adenoma and about 2,800 colorectal cancer cases to address these scientific hypotheses in an extremely time- and cost- effective manner. This study may provide better insight on the nature of family history and provide useful cancer prevention guideline for the highly susceptible population of those with a family history. This proposed work will also provide opportunities for the first epidemiologic evaluation of alcohol and colorectal cancer risk by folate fortification status, which will clarity the involvement and importance of alcohol on one-carbon metabolism and determine the effect of alcohol consumption on colorectal cancer in current high-folate intake status. Public Health Relevance: In this proposed work, we intend to explore the influence of inherited and dietary factors on the association between alcohol consumption and colorectal adenoma/cancer in large epidemiological studies of women and men. By clarifying the role of these factors on alcohol and colorectal cancer risk, this study can help identifying populations susceptible to the adverse effect of alcohol and guiding people in cancer prevention.